Monoclonal antibodies have been shown to represent an important class of therapeutic proteins with applications in various disease states. The goal of GenPharm's program is to inactivate the endogenous mouse immunoglobulin (Ig) repertoire to ensure the generation of purely human antibodies from human Ig transgenics, enabling the production of therapeutic human monoclonal antibodies from mice. Human antibodies will provide a safer and more effective alternative to the rodent antibodies now being developed and used as therapeutic agents. Inactivation of the Ig heavy chain and one of the light chain loci (kappa) has been carried out in Phase I. The goal of Phase II is to provide a completely null Ig background in the form of mice and ES cells homozygous for inactivation of all three Ig loci (heavy chain, kappa and lambda light chain), into which will be introduced, respectively, the human Ig minilocus and yeast artificial chromosome (YAC) transgenes under development at GenPharm. The generation of a fully null Ig genotype will enable the synthesis of human antibodies in the absence of competition from mouse Igs, and will eliminate the extremely time-consuming breeding programs currently required for introducing transgenes into the Ig deficient backgrounds, considerably accelerating the rate at which transgene function can be assessed. In addition, the Ig-deficient mice also provide a potentially valuable model system for the in vivo analysis of B cell development and function.